CYP3A5 Contributes significantly to CYP3A-mediated drug oxidations in liver microsomes from Japanese subjects

Drug Metab Pharmacokinet. 2004 Apr;19(2):120-9. doi: 10.2133/dmpk.19.120.


The purpose of this study was to evaluate a contribution of polymorphic cytochrome P450 (CYP) 3A5 to the oxidation of diltiazem, midazolam and testosterone by liver microsomes from Japanese subjects. Twenty-seven liver samples were classified into three groups according to the CYP3A5 genotypes; CYP3A5(*)1/(*)1 (n=3), (*)1/(*)3 (n=12) and (*)3/(*)3 (n=12). The results of genotyping and immunochemical quantitation of CYP3A5 protein showed a good accordance between the CYP3A5 genotype and CYP3A5 content but not CYP3A4 content in liver microsomes. The expression levels of hepatic CYP3A5 protein ranged from 20 to 60% of the sum of CYP3A4 and CYP3A5 contents in subjects with at least one wild type allele ((*)1). The CYP3A5 contents correlated well with liver microsomal activities of diltiazem N-demethylation, midazolam 1'- and 4-hydroxylations and testosterone 6beta-hydroxylation among subjects carrying at least one (*)1 allele. In addition, the correlation coefficients of CYP3A5 contents with the rates of diltiazem N-demethylation, midazolam 1'-hydroxylation and testosterone 6beta- hydroxylation were higher than those of CYP3A4, although the value of CYP3A5 with the midazolam 4-hydroxylation rate was similar to that of CYP3A4. Kinetic analyses revealed a biphasic diltiazem N-demethylation in liver microsomes from subjects carrying the (*)1 allele. The apparent V(max)/K(m) values for recombinant CYP3A5 indicated the greater contributions to diltiazem N-demethylation and midazolam 1'-hydroxylation as compared with CYP3A4. These results suggest that polymorphic CYP3A5 contributes markedly to the drug oxidations, particularly diltiazem N-demethylation, midazolam 1'- hydroxylation and testosterone 6beta-hydroxylation by liver microsomes from Japanese subjects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium Channel Blockers / metabolism
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytochrome P-450 Enzyme System / metabolism*
  • DNA / genetics
  • DNA Primers
  • Dealkylation
  • Diltiazem / metabolism
  • Escherichia coli / metabolism
  • GABA Modulators / metabolism
  • Genotype
  • Humans
  • Hydroxylation
  • In Vitro Techniques
  • Japan
  • Kinetics
  • Microsomes, Liver / enzymology*
  • Midazolam / metabolism
  • NADPH-Ferrihemoprotein Reductase / genetics
  • NADPH-Ferrihemoprotein Reductase / metabolism
  • Oxidation-Reduction
  • Pharmaceutical Preparations / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Testosterone / metabolism


  • Calcium Channel Blockers
  • DNA Primers
  • GABA Modulators
  • Pharmaceutical Preparations
  • Testosterone
  • DNA
  • Cytochrome P-450 Enzyme System
  • CYP3A protein, human
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • NADPH-Ferrihemoprotein Reductase
  • Diltiazem
  • Midazolam